NFIX influences stem and progenitor lineage fate

The commitment of stem and progenitor cells toward specific hematopoietic lineages is tightly controlled by a number of transcription factors that regulate a differentiation program via the expression of lineage restricting genes. Here we report an important role of the transcription factor Nuclear factor one X (NFIX) in B- and myeloid lineage commitment and differentiation. Ectopic NFIX expression repressed the differentiation of pro-B cells and favoured myeloid cell differentiation thus acting as a regulator of lineage specification in the hematopoietic system. Reciprocally, NFIX deficient bone marrow cells display an increase in B cells and a concomitant decrease in myeloid cells, consistent with a role for NFIX in stem and progenitor lineage fate. The expression of NFIX was transcriptionally downregulated as B cells commit and differentiate and we show that ectopic NFIX expression in vivo blocked B cell development in favour of myelopoiesis. Under B cell specific culture conditions NFIX was able to promote myeloid differentiation of total bone marrow cells but not when expressed specifically in the hematopoietic stem cell (HSC). In myeloid permissive conditions, NFIX promoted the differentiation of mature myeloid cells from the HSC stage of development. The lineage choice in NFIX expressing cells correlated with transcriptional changes in a number of genes, such as E2A, C/EBPalpha, and Id genes. In vivo and in vitro loss of function studies support these data and highlight a novel and critical role for NFIX transcription factor in hematopoiesis and in lineage specification. This work was funded by Howat Foundation, Children with Cancer UK, Science Foundation Ireland PIYRA award, MRC, NYSTEM, and Children Leukaemia Research Project